Airway epithelial regulation of fibroblast hyaluronan and versican production in asthmatic airway inflammation

哮喘气道炎症中成纤维细胞透明质酸和多功能蛋白聚糖产生的气道上皮调节

基本信息

批准号：
9385687
负责人：
STEPHEN R REEVES
金额：
$ 16.23万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9385687
关键词：
Adherence Adhesions Affect Anti-Inflammatory Agents Anti-inflammatory Area Asthma Automobile Driving Autopsy Basic Science Binding Cells Cellular biology Child Childhood Childhood Asthma Clinical Clinical Research Coculture Techniques Data Data Analyses Deposition Development Dinoprostone Disease Environment Enzymes Epithelial Epithelial Cells Epithelium Equilibrium Extracellular Matrix Fibroblasts Funding Genes Germ Cells Goals Healthcare Human Hyaluronan In Vitro Inflammatory Investigation K-Series Research Career Programs Laboratories Lead Leukocytes Lung Maintenance Measures Mentors Mentorship Mesenchymal Methodology Modeling Molecular Weight Monoclonal Antibodies Pathogenesis Phenotype Play Process Production Property Proteomics Public Health Publications Pulmonology Recruitment Activity Regulation Research Research Personnel Resources Respiratory physiology Role Scientist Signal Transduction Specimen Techniques Testing Training Transforming Growth Factor beta United States National Institutes of Health Universities Washington Work Wound Healing airborne allergen airway epithelium airway hyperresponsiveness airway inflammation airway obstruction airway remodeling asthmatic asthmatic airway base career career development cytokine eosinophil in vivo Model indexing innovation interest knock-down leukocyte activation mast cell migration monocyte neutrophil novel therapeutic intervention pediatric department permissiveness professor symposium translational approach versican

项目摘要

PROJECT SUMMARY / ABSTRACT This project is a NIH Mentored Clinical Scientist Research Career Development Award (K08) application for Dr. Stephen Reeves, an Acting Assistant Professor in the Department of Pediatrics at the University of Washington (UW). Dr. Reeves has completed his clinical training in Pediatric Pulmonary Medicine and has both a clinical and research interest in the treatment of pediatric asthma. Dr. Reeves’ specific research interest is understanding the role played by the airway epithelial cells (AECs) in regulating the production of extra- cellular matrix (ECM) by airway mesenchymal cells and alterations in this process that may predispose to airway inflammation. His long-term career goal is to establish himself as an independently-funded principle investigator studying these mechanisms in human cells using basic science and translational approaches. In order to achieve this goal, Dr. Reeves is requesting the NIH K08 support for additional training and mentorship in the following specific areas: (1) additional training in airway cell biology including cell-cell and cell-matrix interactions; (2) additional training in the methodology of ECM characterization and quantitation; (3) additional training in laboratory techniques related to gene knockdown and gene editing; (4) additional training in proteomic approaches and data analysis; (5) attendance of scientific conferences, career development seminars, and additional classroom-based training relevant to this project; and (6) mentorship in the development of an independent research focus with a goal of transitioning to scientific independence. In the present application, Dr. Reeves proposes studies to further investigate the role that AEC signaling plays in driving HA and VCAN deposition in the ECM by HLF. These studies will focus on following areas: Specific Aim 1) determining if primary asthmatic AECs drive HLFs to produce an ECM enriched in HA and VCAN as compared to AECs from healthy children; Specific Aim 2) determining if a HA- and VCAN-enriched ECM produced by HLFs conditioned by asthmatic AECs increases leukocyte adhesion, migration, and activation, as compared to ECM produced by HLFs co-cultured with healthy AECs; Specific Aim 3) determining if clinical indices of lung function and airway inflammation among AEC donors correlate with HA and VCAN accumulation in ECM, and with enhanced leukocyte adhesion, migration, and activation by ECM produced by co-cultured HLFs. These studies hold promise in furthering our understanding of how AECs may regulate ECM deposition by HLFs that ultimately protect against or predispose to inflammatory changes, which is at the present poorly understood. Furthermore, it is anticipated these studies would provide the publications and preliminary data needed to develop an independent research direction and apply for R01 funding at the end of the career development support.

项目摘要 /摘要该项目是NIH指导的临床科学家研究职业发展奖（K08）博士的申请。斯蒂芬·里夫斯（Stephen Reeves），大学儿科学系的代理助理教授华盛顿（UW）。里夫斯博士已经完成了他在儿科肺医学方面的临床培训对小儿哮喘治疗的临床和研究兴趣。里夫斯博士的特定研究兴趣是否了解气道上皮细胞（AEC）在确定外部产生的作用气道杂质细胞的细胞基质（ECM）和在此过程中的改变，可能易见气道炎症。他的长期职业目标是将自己确立为独立资助的原则研究人员使用基础科学和翻译方法在人类细胞中研究这些机制。为了实现这一目标，里夫斯博士要求NIH K08支持其他培训，在以下特定领域中的脑膜：（1）在气道细胞生物学中进行的额外培训，包括细胞细胞和细胞 - 矩阵相互作用；（2）对ECM表征和定量方法的额外培训；（3）与基因敲低和基因编辑有关的实验室技术的额外培训；（4）额外的培训在蛋白质组学方法和数据分析中；（5）科学会议的出席，职业发展 SEMIAR和与该项目相关的其他基于课堂的培训；（6）开发独立研究重点，目的是将其转变为科学独立性。在本应用中，Reeves博士提出研究，以进一步研究AEC信号发挥的作用 HLF在ECM中驱动HA和VCAN沉积时。这些研究将集中于以下领域：具体目标1）确定主要哮喘AEC是否驱动HLFS生成富含HA和VCAN的ECM 与健康儿童的AEC相比；特定目的2）确定富含HA和VCAN的ECM是否由哮喘AEC调节的HLF产生的人白细胞粘合剂，迁移和激活增加与HLFS生产的ECM相比，与健康的AEC共同培养；特定目标3）确定是否临床 AEC供体之间的肺功能和气道注射指标与HA和VCAN相关 ECM积累，并具有增强的白细胞粘合剂，迁移和ECM激活共培养的HLF。这些研究有望进一步发展我们对AEC如何调节ECM的理解 HLF的沉积最终预防或易于炎症变化，这是现在理解不足。此外，预计这些研究将提供出版物和开发独立研究方向所需的初步数据并在结束时申请R01资金职业发展支持。